Endocrine disrupting compounds (EDCs) are hormonally active, synthetic or natural chemicals that interfere with normal functioning of the endocrine system. Exposure to EDCs continues to be a significant and contentious public health issue. Because of the universal and crucial role estradiol plays in reproduction and other biologic processes, estrogenic pollutants in the environment are of particular concern. Given that sex steroids play a crucial role in organ differentiation during development, it is reasonable to expect in utero exposure to exogenous estrogen mimics may alter the developmental trajectory of the fetus. Our preliminary studies using sheep as a model revealed that prenatal exposure to the plasticizer bisphenol A (BPA), an environmentally pervasive estrogenic EDC, at levels approaching that found in human maternal blood and amniotic fluids, resulted in low birth weight female offspring. In this proposal, we will test the following hypotheses: Poor pregnancy outcomes and low birthweight offspring in humans are related to increased exposure to BPA. Experimentally, treatment of pregnant sheep with BPA, at levels approaching those found in human maternal and fetal circulation, would reduce fetal IGF bioavailability and culminate in fetal growth retardation and low birth weight offspring. Even more importantly, the programming effects of BPA on fetal developmental trajectory are transgenerationally transferable. Three Specific Aims will test these hypotheses. In Specific Aim 1 we will measure BPA concentrations in maternal and cord blood of US women and correlate it with pregnancy outcome and birthweight of offspring. In Specific Aim 2, we will determine if BPA, at levels found in human maternal circulation, reduces fetal IGF bioavailability and culminates in intrauterine growth restriction and low birthweight offspring. In Specific Aim3, we will determine if detrimental effects of BPA on fetal growth trajectory are transgenerationally transferable. The research proposed here has important implications for reducing poor pregnancy outcomes by identifying potentially modifiable risk factors for IUGR and low birth weight. Environmental exposures are good candidates for modifiable risk factors as they can be effectively regulated at the personal, behavioral, as well as the regulatory levels. PUBLIC HEALTH RELEVANCE: Endocrine disrupting compounds (EDC) are hormonally active, synthetic or natural chemicals that interfere with normal functioning of the endocrine system. Exposure to EDCs continues to be a significant and contentious public health issue. This proposal will determine 1) to what extent human fetuses are exposed to BPA and if a relationship exists between level of BPA exposure and pregnancy outcomes, 2) if exposure of pregnant sheep to BPA at levels seen in human circulation will lead to low birthweight offspring by altering growth factor availability, and 3) if the effects of BPA on fetal development is carried across subsequent generations.